Abstract COVID-19, caused by novel coronavirus SARS-CoV-2, has recently affected over 600,000 people and has caused more than 30,000 deaths worldwide. Dysregulated immune responses against SARS-CoV-2 virus are a critical component of COVID-19 that can lead to severe respiratory failure (SRF). The dysregulated type 1 interferon (IFN-I) production by innate immune cells are likely involved in immunopathogenesis. However, the molecular mechanisms by which the virus causes lethality are not known. It has been found that COVID-19 patients with SRF exhibit a cytokine storm with hyper activated T cells characterized by pro-inflammatory cytokine production of GM-CSF, IFN-?, and TNF-?, though paradoxically, the T cells express high level of co- inhibitory receptors that are thought to limit this aberrant response. These data indicate there are inadequate inhibitory signals on T cells in severe disease. We have identified TIGIT as a critical co-inhibitory receptor expressed on T cells that plays a central role in orchestrating T cell activation and immune homeostasis in autoimmunity, cancer and viral infection, and its expression was found to be coordinated with the PD-1/TIM-3 module in mice. However, our lab recently discovered that while IFN-I drives expression of this module it surprisingly decreases TIGIT expression in humans implicating a unique function of TIGIT during IFN-I responses on human T cells. Moreover, we developed a gene regulatory network using high resolution transcriptional profiling that allows identification of regulatory factors for co-inhibitory receptor expression during IFN-I response. This leads to our overall hypothesis that delayed IFN-I response to SARS-CoV-2 in older individuals disrupts the T cell co-inhibitory response, leading to T cell hyperactivation and severe illness. Specifically, attenuated TIGIT expression on T cells allows aberrant cytokine release which fuels the cytokine storm in severe COVID-19. Moreover, pre-clinical data demonstrated that TIGIT immunopathology . Thus, our goals are to: 1) identify the molecular signaling limits without affecting viral load in vivo mechanism for the dysregulated immune program leading to hyper T cell responses in COVID-19 patients and to identify potential targets. We will probe dynamic T cell responses by incorporating comprehensive multi- omics single cell analysis in patients with mild and severe manifestation of COVID-19 compared to healthy individuals; 2) we will explore the mechanism for driving hyperactivation of T cells in severe COVID-19. Our previously established gene regulatory network for IFN-I response on T cells will be integrated with data acquired from our single cell analysis. This will allow us to identify the key regulatory factors controlling TIGIT expression under IFN-I response and may allow the identification of novel therapeutic targets; 3) Finally, we will determine the therapeutic potential of TIGIT mediated co-inhibitory signaling in COVID-19 by investigating whether agonistic TIGIT antibodies can ameliorate the hyperactivated state of T cells in severe COVID-19 patients. Studying how co-inhibitory signals modulate T cell responses to SARS-CoV-2 may reveal novel molecular targets for COVID-19 immunotherapy.